Trace and contextual fear conditioning is enhanced in mice lacking the alpha4 subunit of the GABA(A) receptor

Abstract

The GABA(A)R alpha4 subunit is highly expressed in the dentate gyrus region of the hippocampus at predominantly extra synaptic locations where, along with the GABA(A)R delta subunit, it forms GABA(A) receptors that mediate a tonic inhibitory current. The present study was designed to test hippocampus-dependent and hippocampus-independent learning and memory in GABA(A)R alpha4 subunit-deficient mice using trace and delay fear conditioning, respectively. Mice were of a mixed C57Bl/6J X 129S1/X1 genetic background from alpha4 heterozygous breeding pairs. The alpha4-knockout mice showed enhanced trace and contextual fear conditioning consistent with an enhancement of hippocampus-dependent learning and memory. These enhancements were sex-dependent, similar to previous studies in GABA(A)R delta knockout mice, but differences were present in both males and females. The convergent findings between alpha4 and delta knockout mice suggests that tonic inhibition mediated by alpha4betadelta GABA(A) receptors negatively modulates learning and memory processes and provides further evidence that tonic inhibition makes important functional contributions to learning and behavior.

Figure 1. Experimental Design

(A) Outline of three-day procedure. (B) Diagram depicting temporal relationship between tone and shock in delay vs. trace conditioning.

Figure 2. GABA_AR α4 KO mice show no differences in delay tone fear conditioning

Mean (± SEM) percent freezing of α4 KO and WT mice during the BL, tone, and trace intervals of the tone test for delay conditioned animals.

Figure 3. GABA_ARα4 KO mice exhibit an enhancement of trace tone fear conditioning

Mean (± SEM) percent freezing of α4 KO and WT mice during the BL, tone, and trace intervals of the tone test for trace conditioned animals.

Figure 4. The enhancement of context fear in GABA_ARα4 KO mice depends on both sex and type of tone conditioning

(A) Mean (± SEM) percent freezing of male α4 KO and WT mice during the context test. (B) Mean (± SEM) percent freezing of female α4 KO and WT mice during the context test.

Figure 4. The enhancement of context fear in GABA_ARα4 KO mice depends on both sex and type of tone conditioning

(A) Mean (± SEM) percent freezing of male α4 KO and WT mice during the context test. (B) Mean (± SEM) percent freezing of female α4 KO and WT mice during the context test.